NAVELBINE® 20 mg soft capsule

Each soft capsule contains 20mg vinorelbine as tartrate

For a full list of excipients, see section 6.1

Soft capsule.

Light brown soft capsule printed N20.

As a single agent or in combination for:

• The first line treatment of stage 3 or 4 non small cell lung cancer.

• The treatment of advanced breast cancer stage 3 and 4 relapsing after or refractory to an anthracycline containing regimen.

In adult patients

As a single agent, the recommended regimen is:

First three administrations

60mg/m² of body surface area, administered once weekly

Subsequent administrations

Beyond the third administration, it is recommended to increase the dose of Navelbine to 80mg/m² once weekly except in those patients for whom the neutrophil count dropped once below 500/mm³ or more than once between 500 and 1000/mm³ during the first three administrations at 60mg/m².

Dose modification

For any administration planned to be given at 80mg/m², if the neutrophil count is below 500/mm³ or more than once between 500 and 1000 / mm³ the administration should be delayed until recovery and the dose reduced from 80 to 60mg/m² per week during the 3 following administrations.

If the neutrophil count is below 1500 /mm³ and/or the platelet count below 100000/mm³, then the treatment should be delayed until recovery.

It is possible to re-escalate the dose from 60 to 80 mg/m² per week if the neutrophil count did not drop below 500/mm³ or more than once between 500 and 1000/mm³ during 3 administrations given at 60 mg/m² according to the rules previously defined for the first 3 administrations.

For combination regimens, the dose and schedule will be adapted to the treatment protocol.

Based on clinical studies, the oral dose of 80 mg/m² was demonstrated to correspond to 30 mg/m² of the iv form and 60 mg/m² to 25 mg/m².

This has been the base for combination regimens alternating iv and oral forms improving patient convenience.

Capsules of different strengths (20, 30, 80 mg) are available in order to choose the adequate combination for the right dosage.

The following table gives the dose required for appropriate ranges of body surface area (BSA).

Even for patients with BSA 2 m2 the total dose should never exceed 120 mg per week at 60 mg /m2 and 160 mg per week at 80 mg/m2.

Administration

Navelbine must be given strictly by the oral route.

Navelbine must be swallowed whole with water, without chewing, sucking or dissolving the capsule.

It is recommended to administer the capsule with some food.

Administration in the elderly

Clinical experience has not detected any significant differences among elderly patients with regard to the response rate, although greater sensitivity in some of these patients cannot be excluded. Age does not modify the pharmacokinetics of vinorelbine: see section 5.2.

Administration in children

Safety and efficacy in children have not been established and administration is therefore not recommended.

Administration in patients with liver insufficiency

Navelbine can be administered at the standard dose of 60 mg/m²/week in patients with mild liver impairment (bilirubin < 1.5 x ULN, and ALAT and/or ASAT from 1.5 to 2.5 x ULN). In patients with moderate liver impairment (bilirubin from 1.5 to 3 x ULN, whatever the levels of ALAT and ASAT), Navelbine should be administered at a dose of 50 mg/m²/week. The administration of Navelbine in patients with severe hepatic impairment is contra-indicated: see sections 4.3, 4.4, 5.2.

Administration in patients with renal insufficiency

Given the minor renal excretion, there is no pharmacokinetic justification for reducing the dose of Navelbine in patients with serious renal insufficiency: see sections 4.4, 5.2.

Specific instructions must be observed for handling Navelbine: see section 6.6

- Known hypersensitivity to vinorelbine or other vinca-alkaloids or to any of the constituents.

- Disease significantly affecting absorption

- Previous significant surgical resection of stomach or small bowel.

- Neutrophil count < 1500/mm³ or severe infection current or recent (within 2 weeks).

- Platelet count < 100000/mm³

- Severe hepatic insufficiency

- Pregnancy: see section 4.6

- Lactation: see section 4.6

- Patients requiring long-term oxygen therapy

- In combination with yellow fever vaccine: see section 4.5

Special warnings

Navelbine should be prescribed by a physician who is experienced in the use of chemotherapy with facilities for monitoring cytotoxic drugs.

If the patient chews or sucks the capsule by error, the liquid is an irritant. Proceed to mouth rinses with water or preferably a normal saline solution.

In the event of the capsule being cut or damaged, the liquid content is an irritant, and so may cause damage if in contact with skin, mucosa or eyes. Damaged capsules should not be swallowed and should be returned to the pharmacy or to the doctor in order to be properly destroyed. If any contact occurs, immediate thorough washing with water or preferably with normal saline solution should be undertaken.

In the case of vomiting within a few hours after drug intake, do not re-administer. Supportive treatment such as metoclopramide or 5HT₃ antagonists (e.g. ondansetron, granisetron) may reduce the occurrence of this: see section 4.5. Navelbine soft capsule is associated with a higher incidence of nausea/vomiting than the intravenous formulation. Primary prophylaxis with antiemetics and administration of the capsules with some food is recommended as this has also been shown to reduce the incidence of nausea and vomiting: see section 4.2.

Patients receiving concomitant morphine or opioid analgesics: laxatives and careful monitoring of bowel mobility are recommended. Prescription of laxatives may be appropriate in patients with prior history of constipation.

Due to sorbitol content, patients with rare hereditary problems with fructose intolerance should not take the capsules.

Close haematological monitoring must be undertaken during treatment (determination of haemoglobin level and the leucocyte, neutrophil and platelet counts on the day of each new administration).

Dosing should be determined by haematological status:

- If the neutrophil count is below 1500 /mm³ and/or the platelet count is below 100000/mm³, then the treatment should be delayed until recovery.

- For dose escalation from 60 to 80 mg/m² per week, after the third administration: see section 4.2.

- For the administrations given at 80mg/m², if the neutrophil count is below 500/mm³ or more than once between 500 and 1000 /mm³, then the treatment should be delayed until recovery. The administration should not only be delayed but also reduced to 60mg/m² per week. It is possible to reescalate the dose from 60 to 80 mg/m² per week: see section 4.2.

During clinical trials where treatments were initiated at 80 mg/m², a few patients developed excessive neutropenic complications including those with a poor performance status. Therefore it is recommended that the starting dose should be 60 mg/m² escalating to 80 mg/m² if the dose is tolerated as described in section 4.2.

If patients present signs or symptoms suggestive of infection, a prompt investigation should be carried out.

Special precautions for use

Special care should be taken when prescribing for patients with:

- history of ischemic heart disease: see section 4.8

- poor performance status

Navelbine should not be given concomitantly with radiotherapy if the treatment field includes the liver.

This product is specifically contra-indicated with yellow fever vaccine and its concomitant use with other live attenuated vaccines is not recommended: see section 4.3.

Caution must be exercised when combining Navelbine and strong inhibitors or inducers of CYP3A4 (see section 4.5), and its combination with phenytoin (like all cytotoxics) and with itraconazole (like all vinca alkaloids) is not recommended.

Oral Navelbine was studied in patients with liver impairment at the following doses:

- 60 mg/m² in 7 patients with mild liver impairment (bilirubin < 1.5 x ULN, and ALAT and/or ASAT from 1.5 to 2.5 x ULN);

- 50 mg/m² in 6 patients with moderate liver impairment (bilirubin from 1.5 to 3 x ULN, whatever the levels of ALAT and ASAT).

Total clearance of vinorelbine was neither modified between mild and moderate liver impairment nor was it altered in hepatically impaired patients when compared with clearance in patients with normal liver function.

Oral Navelbine was not studied in patients with severe hepatic impairment therefore its use is contra-indicated in these patients: see sections 4.2, 4.3, 5.2.

As there is a low level of renal excretion there is no pharmacokinetic rationale for reducing the dose of Navelbine in patients with impaired kidney function: see sections 4.2, 5.2.

Concomitant use contraindicated

Yellow fever vaccine: as with all cytotoxics, risk of fatal generalised vaccine disease: see section 4.3.

Concomitant use not recommended

Live attenuated vaccines: (for yellow fever vaccine, see concomitant use contraindicated) as with all cytotoxics, risk of generalised vaccine disease, possibly fatal. This risk is increased in patients already immunodepressed by their underlying disease. It is recommended to use an inactivated vaccine when one exists (e.g. poliomyelitis): see section 4.4

Phenytoin: as with all cytotoxics, risk of exacerbation of convulsions resulting from the decrease of phenytoin digestive absorption by cytotoxic drug or risk of toxicity enhancement or loss of efficacy of the cytotoxic drug due to increased hepatic metabolism by phenytoin.

Itraconazole: as with all vinca-alkaloids, increased neurotoxicity of vinca-alkaloids due to the decrease of their hepatic metabolism.

Concomitant use to take into consideration

Cisplatin: There is no mutual pharmacokinetic interaction when combining Navelbine with cisplatin over several cycles of treatment. However, the incidence of granulocytopenia associated with Navelbine use in combination with cisplatin is higher than associated with Navelbine single agent.

Mitomycin C: risk of bronchospasm and dyspnoea are increased, in rare case an interstitial pneumonitis was observed.

Ciclosporin, tacrolimus: excessive immunodepression with risk of lymphoproliferation.

As vinca-alkaloids are known as substrates for P-glycoprotein, and in the absence of specific study, caution should be exercised when combining Navelbine with strong modulators of this membrane transporter.

The combination of NAVELBINE with other drugs with known bone marrow toxicity is likely to exacerbate the myelosuppressive adverse effects.

No clinically significant pharmacokinetic interaction was observed when combining Navelbine with several other chemotherapeutic agents (paclitaxel, docetaxel, capecitabine and oral cyclophosphamide).

As CYP3A4 is mainly involved in the metabolism of vinorelbine, combination with strong inhibitors of this isoenzyme (e.g. azole antifungals such as ketoconazole and itraconazole) could increase blood concentrations of vinorelbine and combination with strong inducers of this isoenzyme (e.g. rifampicin, phenytoin) could decrease blood concentrations of vinorelbine.

Anti-emetic drugs such as 5HT₃ antagonists (e.g. ondansetron, granisetron) do not modify the pharmacokinetics of Navelbine soft capsules (see section 4.4).

Anticoagulant treatment: as with all cytotoxics, the frequency of INR (International Normalised Ratio) monitoring should be increased due to the potential interaction with oral anticoagulants and increased variability of coagulation in patients with cancer.

Food does not modify the pharmacokinetics of vinorelbine.

Pregnancy

Navelbine is suspected to cause serious birth effects when administered during pregnancy: see section 5.3.

Navelbine is contra-indicated in pregnancy: see section 4.3.

In case of a vital indication for treatment with Navelbine during pregnancy a medical consultation concerning the risk of harmful effects for the child should be conducted. If pregnancy occurs during treatment genetic counseling should be offered.

Women of child-bearing potential

Women of child-bearing potential must use effective contraception during treatment and up to 3 months after treatment: see section 4.3

Lactation

It is unknown whether vinorelbine is excreted in human breast milk.

The excretion of vinorelbine in milk has not been studied in animal studies.

A risk to the suckling child cannot be excluded therefore breast feeding must be discontinued before starting treatment with Navelbine: see section 4.3.

Fertility

Men being treated with Navelbine are advised not to father a child during and minimally up to 3 months after treatment: see section 4.3.

Prior to treatment advice should be sought for conserving sperm due to the chance of irreversible infertility as a consequence of treatment with vinorelbine.

No studies on the effects on the ability to drive and use machines have been performed but on the basis of the pharmacodynamic profile vinorelbine does not affect the ability to drive and use machines. However, caution is necessary in patients treated with vinorelbine considering some adverse effects of the drug: see section 4.8.

The overall reported frequency of undesirable effects was determined from clinical studies in 316 patients (132 patients with non small cell lung cancer and 184 patients with breast cancer) who received the recommended regimen of Navelbine (first three administrations at 60mg/m²/week followed by 80mg/m²/week).

Adverse reactions reported are listed below, by system organ and by frequency.

Additional Adverse reactions from Post Marketing experience has been added according to the MedDRA classification with the frequency Not known.

The reactions were described using the NCI common toxicity criteria

Undesirable effects reported with Navelbine soft capsule:

Pre-marketing experience:

The most commonly reported adverse drug reactions are bone marrow depression with neutropenia, anaemia and thrombocytopenia, gastrointestinal toxicity with nausea, vomiting, diarrhoea, stomatitis and constipation. Fatigue and fever were also reported very commonly.

Post-marketing experience:

Navelbine soft capsule is used as single agent or in combination with other chemotherapeutic agents or targeted therapy agents such as cisplatin, capecitabine, carboplatin, epirubicin, trastuzumab, erlotinib, sorafenib.

The most commonly system organ classes involved during post-marketing experience are: 'Blood and lymphatic system disorders', 'Gastrointestinal disorders', 'Infections and infestations' and 'General disorders and administration site conditions'. This information is consistent with the pre-marketing experience.

Undesirable effects with Navelbine, concentrate for infusion:

Some undesirable effects were observed with Navelbine, concentrate for solution for infusion during pre- and post-marketing experience which were not reported with Navelbine soft capsule.

In order to provide the complete information and to further the safety of use of Navelbine soft capsule, these effects are presented below:

Symptoms

Overdosage with Navelbine soft capsules could produce bone marrow hypoplasia sometimes associated with infection, fever, paralytic ileus and hepatic disorders.

Emergency procedure

General supportive measures together with blood transfusion, growth factors, and broad spectrum antibiotic therapy should be instituted as deemed necessary by the physician. A close monitoring of hepatic function recommended.

Antidote

There is no known antidote for overdosage of Navelbine.

Pharmacotherapeutic group: Vinca alkaloïds and analogues (ATC Code: L01C A04)

Navelbine is a antineoplastic drug of the vinca alkaloid family but unlike all the other vinca alkaloids, the catharantine moiety of vinorelbine has been structurally modified. At the molecular level, it acts on the dynamic equilibrium of tubulin in the microtubular apparatus of the cell. It inhibits tubulin polymerization and binds preferentially to mitotic microtubules, affecting axonal microtubules at high concentrations only. The induction of tubulin spiralization is less than that produced by vincristine.

Navelbine blocks mitosis at G2-M, causing cell death in interphase or at the following mitosis.

Safety and efficacy of Navelbine in paediatric patients have not been established. Clinical data from two single-arm Phase II studies using intravenous vinorelbine in 33 and 46 paediatric patients with recurrent solid tumours, including rhabdomyosarcoma, other soft tissue sarcoma, Ewing sarcoma, liposarcoma, synovial sarcoma, fibrosarcoma, central nervous system cancer, osteosarcoma, neuroblastoma at doses of 30 to 33.75mg/m² D1 and D8 every 3 weeks or once weekly for 6 weeks every 8 weeks showed no meaningful clinical activity. The toxicity profile was similar to that reported in adult patients (see section 4.2).

Pharmacokinetic parameters of vinorelbine were evaluated in blood.

Absorption

After oral administration, vinorelbine is rapidly absorbed and the T_max is reached between 1.5 to 3 h with a blood concentration peak (C_max) of approximately 130 ng/ml after a dose of 80 mg/m².

Absolute bioavailability is approximately 40% and a simultaneous intake of food does not alter the exposure to vinorelbine.

Oral vinorelbine at 60 and 80 mg/m² leads to blood exposure comparable to that achieved with intravenous vinorelbine at 25 and 30 mg/m², respectively.

The blood exposure to vinorelbine increases proportionally with the dose up to 100mg/m². Interindividual variability of the exposure is similar after administration by intravenous and oral routes.

Distribution

The steady-state volume of distribution is large, on average 21.2 l.kg^-1(range: 7.5 - 39.7 l.kg^-1), which indicates extensive tissue distribution.

Binding to plasma proteins is weak (13.5%), vinorelbine binds strongly to blood cells and especially to platelets (78%).

There is a significant uptake of vinorelbine in lungs, as assessed by pulmonary surgical biopsies which showed concentration up to a 300- fold higher concentration than in serum. Vinorelbine is not found in the central nervous system.

Biotransformation

All metabolites of vinorelbine are formed by CYP3A4 isoform of cytochromes P450, except 4-O-deacetylvinorelbine likely to be formed by carboxylesterases. 4-O-deacetylvinorelbine is the only active metabolite and the main one observed in blood.

Neither sulfate nor glucuronide conjugates are found.

Elimination

The mean terminal half-life of vinorelbine is around 40 hours. Blood clearance is high, approaching hepatic blood flow, and is 0.72 l.h^-1.kg^-1 (range: 0.32-1.26 l.h^-1.kg^-1).

Renal elimination is low (<5 % of the dose administered) and consists mostly in parent compound. Biliary excretion is the predominant elimination route of both unchanged vinorelbine, which is the main recovered compound, and its metabolites.

Special patients groups

Renal and liver impairment:

The effects of renal dysfunction on the pharmacokinetics of vinorelbine have not been studied. However, dose reduction in case of reduced renal function is not indicated with vinorelbine due to the low level of renal elimination.

Pharmacokinetics of orally administered vinorelbine were not modified after administration of 60 mg/m² in 7 patients with mild liver impairment (bilirubin < 1.5 x ULN, and ALAT and/or ASAT from 1.5 to 2.5 x ULN) and of 50 mg/m² in 6 patients with moderate liver impairment (bilirubin from 1.5 to 3 x ULN, whatever the levels of ALAT and ASAT). Total clearance of vinorelbine was neither modified between mild and moderate impairment nor was it altered in hepatically impaired patients when compared with clearance in patients with normal liver function.

No data is available for patients with severe liver impairment therefore Navelbine is contra-indicated in these patients: see sections 4.2, 4.3 and 4.4.

Elderly patients

A study with oral vinorelbine in elderly patients ( 70 years) with NSCLC demonstrated that pharmacokinetics of vinorelbine were not influenced by age. However, since elderly patients are frail, caution should be exercised when increasing the dose of Navelbine soft capsule: see section 4.2.

Pharmacokinetics/Pharmacodynamic relationships

A strong relationship has been demonstrated between blood exposure and depletion of leucocytes or PMNs.

Pre-clinical data reveal no special hazard for humans based on conventional studies of repeated dose toxicity.

Vinorelbine induced chromosome changes but was not mutagenic in Ames test. It is assumed that vinorelbine can cause mutagenic effects (induction of aneuploidy of polyploidy) in man.

In animal reproductive studies, vinorelbine was embryo-feto-lethal and teratogenic.

No haemodynamic effects were found in dogs receiving vinorelbine at maximal tolerated dose; only some minor, non significant disturbances of repolarisation were observed as with other vinca alkaloids tested.

No effect on the cardiovascular system was observed in primates receiving repeated doses of vinorelbine over 39 weeks.

Fill solution:

Ethanol, anhydrous

Water, purified

Glycerol

Macrogol 400

Shell capsule:

Gelatin

Glycerol 85%

Sorbitol/Sorbitan Anidrisorb 85/70)

Yellow iron oxide E172

Titanium dioxide E171

Triglycerides, medium chain

Phosal 53 MCT (Phosphatidylcholine; Glycerides; Ethanol, anhydrous)

Edible printing ink:

Cochineal extract E120

Hypromellose

Propylene glycol

Not applicable

3 years.

Store at 2° C - 8° C (in a refrigerator). Store in the original container.

Peel-push PVC/PVDC/ aluminium blister.

Pack size: 1 capsule

Any unused product or waste material should be disposed of in accordance with local requirements.

Instructions for use/handling

To open the packaging:

1. Cut the blister along the black dotted line

2. Peel the soft plastic foil off

3. Push the capsule through the aluminium foil.

PIERRE FABRE Limited

Hyde Abbey House

23 Hyde Street

Winchester Hampshire S023 7DR

United Kingdom

PL 00603/0029

Date of first authorisation: 31^st March 2005

Renewal of authorisation: 30^th March 2010

28/07/2011